Safety and Efficacy of Edaravone Dexborneol Sublingual Tablets for Blood-Brain Barrier Dysfunction in CADASIL

Official title

Safety and Efficacy of Edaravone Dexborneol Sublingual Tablets for Blood-Brain Barrier Dysfunction in CADASIL: A Single-Center, Prospective, Single-Arm, Self-Controlled Clinical Trial.

Overview

This study is a single-center, prospective, single-arm, self-controlled clinical trial designed to assess the safety and efficacy of edaravone dexborneol sublingual tablets for blood-brain barrier (BBB) dysfunction in patients with CADASIL. The study will enroll approximately 60 participants aged 18 to 80 years with genetically confirmed CADASIL. Participants will be followed for a total duration of 12 months, including two consecutive phases. * Phase 1 is a 6-month natural history observation period, during which participants do not receive the study drug and continue their routine standard care for CADASIL. * Phase 2 is a 6-month drug intervention period, in which participants will receive edaravone dexborneol sublingual tablets to investigate the effect on the BBB water exchange rate (kw), measured by diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL) MRI, and to assess potential benefits on stroke risk reduction, cognitive function, and gait performance. The primary endpoint is the change in kw measured by DP-pCASL. Secondary endpoints include the incidence of clinical stroke events; changes in neuropsychological performance, MRI-based CSVD biomarkers, gait and motor assessments, functional disability and activities-of-daily-living scales, and peripheral blood biomarkers. Safety assessments will include adverse events (AEs) and serious adverse events (SAEs).

Detailed description

This study is a single-center, prospective, single-arm, self-controlled clinical trial evaluating the safety and efficacy of edaravone dexborneol sublingual tablets for blood-brain barrier (BBB) dysfunction in CADASIL patients.

1. Background and Rationale CADASIL is the most common monogenic form of cerebral small vessel disease (CSVD), caused by pathogenic mutations in the NOTCH3 gene. BBB dysfunction is increasingly recognized as one of the core pathophysiological mechanisms in CADASIL, contributing to white matter injury, progressive cognitive decline, and recurrent stroke, and represents a potential therapeutic target. Edaravone Dexborneol, a novel free radical scavenger and anti-inflammatory agent, has shown neuroprotective effects in preclinical models and clinical trials for ischemic stroke. The TASTE-SL trial demonstrated that edaravone dexborneol improved 90-day functional outcomes in patients with acute ischemic stroke. Based on these findings, this study is designed to systematically assess the efficacy and safety of edaravone dexborneol sublingual tablets in ameliorating BBB dysfunction in patients with CADASIL, and to investigate their potential benefits in reducing stroke risk and improving cognitive function. 2. Study Design and Methods A total of 60 participants aged 18 to 80 years with genetically confirmed CADASIL will be recruited. The primary endpoint is the change in the BBB water-exchange rate (kw), measured by diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL) MRI. The trial consists of two sequential phases: during the first 6 months (natural disease observation period), participants do not receive the study drug and continue their routine standard care for CADASIL, allowing for the characterization of intra-individual natural variability of kw. During the subsequent 6 months (treatment period), all participants will receive edaravone dexborneol sublingual tablets in addition to their routine standard care, and treatment-related changes in kw will be evaluated. All participants will undergo multimodal MRI scanning at baseline, month 6, and month 12, along with comprehensive assessments including cognitive testing, clinical scales, and peripheral blood biomarkers. 3. Significance This study is expected to fill a significant gap in pharmacological intervention research for CADASIL and provide clinical evidence supporting the potential extension of edaravone dexborneol to genetically mediated small vessel disease.

Interventions

• Drug Edaravone Dexborneol Sublingual Tablets
  One tablet (containing edaravone 30 mg and dexborneol 6 mg) is taken sublingually twice daily for the 6-month treatment period.

Primary outcome measures

• Change in whole-brain blood-brain barrier water exchange rate (kw) measured by DP-pCASL MRI [Time frame: Baseline, Month 6, and Month 12]

Secondary outcome measures (12)

• Clinical Stroke Events [Time frame: 12 months]
• Change in Montreal Cognitive Assessment (MoCA) Score [Time frame: Baseline, Month 6, and Month 12]
• Change in Auditory Verbal Learning Test (AVLT) Score [Time frame: Baseline, Month 6, and Month 12]
• Change in Boston Naming Test Score [Time frame: Baseline, Month 6, and Month 12]
• Change in Stroop Color-Word Test completion time [Time frame: Baseline, Month 6, and Month 12]
• Change in Stroop Color-Word Test number of correct responses [Time frame: Baseline, Month 6, and Month 12]
• Change in Symbol Digit Modalities Test (SDMT) Score [Time frame: Baseline, Month 6, and Month 12]
• Change in Trail Making Test (TMT) Score [Time frame: Baseline, Month 6, and Month 12]
• Change in Digit Span Test (DST) Score [Time frame: Baseline, Month 6, and Month 12]
• Change in Hamilton Anxiety Rating Scale (HAMA) score [Time frame: Baseline, Month 6, and Month 12]
• Change in Hamilton Depression Rating Scale (HAMD) score [Time frame: Baseline, Month 6, and Month 12]
• Change in number of lacunes [Time frame: Baseline, Month 6, and Month 12]

Eligibility criteria

Inclusion criteria

• 1\. Genetically Confirmed CADASIL: Diagnosis of CADASIL confirmed by NOTCH3 genetic testing.
• 2\. Age: Between 18 and 80 years.
• 3\. Lacunar Lesion Requirement: Presence of ≥1 lacune on brain MRI.
• 4\. No acute ischemic stroke or intracerebral hemorrhage within the past 3 months.
• 5\. Modified Rankin Scale (mRS) score of 0 to 3.
• 6\. Contraception Requirements: Women of childbearing potential and male participants with female partners of childbearing potential must agree to use effective contraception during the study and 30 days after the last dose of the investigational drug.Female participants must have a negative pregnancy test before enrollment.
• 7\. Informed Consent: Participants or their legal representatives must voluntarily sign an informed consent form (ICF).

Exclusion criteria

• 1\. Presence of other major neurological disorders: Non-vascular white matter diseases (e.g., multiple sclerosis, carbon monoxide encephalopathy), central nervous system infections, Creutzfeldt-Jakob disease, primary Parkinson's disease, traumatic brain injury, or intracranial tumors.
• 2\. Severe Liver Dysfunction: Active liver disease (acute hepatitis, chronic active hepatitis, cirrhosis) or ALT/AST >2× ULN.
• 3\. Severe renal impairment (serum creatinine >1.5× ULN).
• 4\. Life Expectancy <1 year due to severe systemic diseases.
• 5\. Contraindications to MRI: Participants with MRI-incompatible implants, severe claustrophobia, or inability to undergo MRI.
• 6\. Known Allergies: History of hypersensitivity to Dexborneol, natural borneol, edaravone, or any excipients (e.g., mannitol, copovidone, microcrystalline cellulose, silica, magnesium stearate).
• 7\. Pregnancy and Lactation: Pregnant or lactating women, or those planning pregnancy during the study period.
• 8\. Participation in Other Clinical Trials
• 9\. Other Investigator-Determined Factors: Any other medical, psychological, or social condition that, in the investigator's judgment, makes the patient unsuitable for participation.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Huashan Hospital, Fudan University — Shanghai

Identifiers

NCT: NCT07692399 · KY2026-703

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗